多发性骨髓瘤（MM）是一种无法治愈的浆细胞恶性肿瘤，促使人们对新的潜在治疗途径进行研究。表没食子儿茶素-3-没食子酸酯 (EGCG) 是绿茶的主要成分，具有抗氧化、抗炎和抗肿瘤特性。此前的研究表明，EGCG 能抑制多发性骨髓瘤细胞的增殖并诱导其凋亡，但其潜在的分子机制尚不清楚。因此，在这项研究中，我们试图探讨 EGCG 对 MM 的治疗效果和潜在机制。最初，使用 CCK8（细胞计数试剂盒-8）测定和膜联蛋白 V-FITC/PI 染色，我们证明 EGCG 剂量依赖性地降低 MM 细胞系 MM.1S 和 RPMI 8226 中的细胞活力并诱导细胞凋亡。随后，mRNA 测序EGCG处理的MM.1S细胞显示与内质网应激（ERS）相关的基因显着上调，包括P-eIF2α（磷酸化真核翻译起始因子2α）、ATF4（激活转录因子4）、CHOP（C/ EBP 同源蛋白（DDIT3）和 PUMA（p53 上调细胞凋亡调节剂，BBC3），通过蛋白质印迹在蛋白水平上得到证实。此外，用 eIF2α 抑制剂 ISRIB 治疗可降低 EGCG 诱导的细胞凋亡率，并促进 MM 细胞中所有四种 ER 应激相关分子的蛋白表达增加。此外，mRNA-seq 数据显示 EGCG 处理的 MM 细胞中 α-微管蛋白 1b (TUBA1B) 表达下调，这一点已通过蛋白质印迹和免疫荧光分析得到证实。此外，我们利用小鼠模型证明 EGCG 可以抑制骨髓瘤肿瘤的生长，而 ISRIB 可以抑制骨髓瘤肿瘤的生长。总之，这项新研究的结果表明，EGCG 通过激活 ER 应激途径和破坏细胞骨架完整性来促进 MM 细胞凋亡。这些发现强调了 EGCG 的多方面抗肿瘤作用及其在 MM 治疗中的潜在临床应用。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Multiple myeloma (MM) is an incurable plasma cell malignancy that has prompted investigations into new potential therapeutic avenues. Epigallocatechin-3-gallate (EGCG), a major component of green tea, confers antioxidant, anti-inflammatory, and anti-tumor properties. Previous studies have shown that EGCG inhibits proliferation and induces apoptosis of multiple myeloma cells, however its underlying molecular mechanisms are largely unknown. In this study, we accordingly sought to examine the therapeutic effects and underlying mechanisms of EGCG on MM. Initially, using CCK8 (Cell Counting Kit-8) assays and Annexin V-FITC/PI staining, we demonstrated that EGCG dose-dependently reduced cell viability and induced apoptosis in the MM cell lines MM.1S and RPMI 8226. Subsequently, mRNA sequencing of EGCG-treated MM.1S cells revealed a significant upregulation of genes associated with endoplasmic reticulum stress (ERS), including P-eIF2α (phosphorylation-eukaryotic translation initiation factor 2 alpha), ATF4 (activating transcription factor 4), CHOP (C/EBP homologous protein, DDIT3), and PUMA (p53 upregulated modulator of apoptosis, BBC3), which were confirmed at the protein level by western blotting. Furthermore, treatment with the eIF2α inhibitor ISRIB reduced the rates of EGCG-induced apoptosis and promoted increases in the protein expression of all four ER stress-related molecules in MM cells. Additionally, mRNA-seq data revealed a downregulation of α-Tubulin 1b (TUBA1B) expression in EGCG-treated MM cells, which was confirmed by western blotting and immunofluorescence analyses. Moreover, we utilized a mouse model to show that EGCG inhibited myeloma tumor growth, which was inhibited by ISRIB. In summary, the findings of this novel study indicated that EGCG promotes apoptosis of MM cells, both via activation of the ER stress pathway and disruption of cytoskeletal integrity. These findings highlight the multi-faceted anti-tumor effects of EGCG and its potential clinical application in MM treatment.Copyright © 2024 Elsevier B.V. All rights reserved.